Viral and non-viral cellular therapies for neurodegeneration

TL;DR

This review explores gene and cell-based therapies for neurodegenerative diseases like Alzheimer's and Parkinson's, focusing on viral vectors, antisense oligonucleotides, and stem cells.

Contribution

The paper provides a comprehensive overview of emerging gene and cell-based therapies for neurodegeneration, highlighting recent targets and strategies.

Findings

Viral vectors like AAVs and lentiviruses are effective for gene delivery in neurodegenerative therapies.

Antisense oligonucleotides show promise in reducing toxic proteins such as tau and α-synuclein.

Stem cell therapies, including MSCs and iPSC-derived neurons, are being tested to replace lost neurons and reduce inflammation.

Abstract

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.

Gene- and cell-based therapies for neurodegenerative diseases are presented in four sections. Viral Vectors: AAV, lentivirus, retrovirus; benefits include crossing the blood-brain barrier and enhancing gene expression. Antisense Oligonucleotides: Aim to reduce toxic protein levels and restore RNA splicing. Stem Cell Therapies: Focus on replacing lost neurons and reducing inflammation. Emerging Targets: Include TREM2, progranulin, GBA, and α-synuclein, targeting amyloid plaques and dysfunctional microglia. An illustration of a brain is centrally placed.

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